Having sold over 1 million copies, it has achieved a landmark rarely reached by books about natural medicine. Two fundamental points made in his book are that, a) sugar is toxic to the brain; and b) nonceliac gluten sensitivity is real. And, with this fifth edition, Perlmutter has been able to update the book with even more supporting scientific evidence.

Newer Evidence Fully Supports Lifestyle-Based Alzheimer's Prevention

As noted by Perlmutter, even though there's no conventional treatment for Alzheimer's, research shows this devastating degenerative neurological disease can be effectively prevented by lowering sugar exposure, increasing exercise and improving the quality of your sleep.

"The science is now completely lined up behind us, showing that our dietary choices are having a huge influence on the decay of the human brain … We're really hammering away at this profound relationship between even mild elevations of blood sugar and risk for dementia.

And certainly, the ideas that we put forward about becoming Type 2 diabetic and quadrupling your risk for Alzheimer's have been validated. The data that we did not have [five years ago] that we have now, with reference to what's causing diabetes, I think is really very intriguing, and is cause for us to take a step back and take a breath.

Because what we're now looking at is powerful data that connects statin use in both males and females with development of diabetes. In males, it's about a 41 percent increased risk of diabetes in statin users [and] … a 71 percent increased risk of developing diabetes in women who are put on a statin medication.

They become diabetic and their risk for Alzheimer's goes up dramatically — as much as three- or fourfold. Do I wish I would have had that information five years ago? Well, it wasn't published, so I didn't have it. But it's really hugely important that we, as physicians, try to practice under the notion of 'Above all, do no harm.'

We are making men and women diabetic and magnifying their risk for Alzheimer's and cardiovascular disease. I mean women have a three to four times increased risk of coronary artery disease if they become diabetic. For men, it's a two- to threefold increase, which is huge … That's new information.

The dietary information … now lines up [with] the idea that fat is actually good for us and that the real relationship that's damaging to us is our relationship with sugar and carbs.

That was our original message that was accepted by most, but certainly experienced a bit of pushback from mainstream medicine that wanted us to believe that we should all be low-fat and no-fat. We now know with great confirmation that [low-fat] is absolutely the wrong approach."

Of the three patients, two did alternating-day 24-hour fasts, while one fasted for 24 hours three times a week over a period of several months. On fasting days, they were allowed to drink unlimited amounts of low-calorie fluids such as water, coffee, tea and bone broth, and to eat a low-calorie, low-carb dinner.

On nonfasting days, they were allowed both lunch and dinner, but all meals were low in sugar and refined carbohydrates throughout. (The complete manual of the fasting regimen used is described in Fung's book, "The Complete Guide to Fasting."4)

Two of the patients were able to discontinue all of their diabetes medications while the third was able to discontinue three of his four drugs. All three also lost between 10 and 18 percent of their body weight. All of these patients had been taking insulin for up to 20 years, yet were able to completely reverse their diabetes through this dietary change alone. Fung is not the only one who has demonstrated this.

"Dr. Sarah Hallberg of Virta Health published a report last year in a study of 100 individuals with Type 2 diabetes … Just putting them on a ketogenic diet reversed diabetes in many, and across the board, dramatically reduced their [need for] medications.

One class of drugs that's commonly used in Type 2 diabetics are sulfonylureas. In [Hallberg's] study, she was able to get 100 percent of the people taking sulfonylureas off of that class of medication. Who knew? Well, we suspected it. Many of us knew. I use that sort of rhetorically. But diet is key.

A ketogenic diet has also been implemented in individuals with early-stage cognitive decline and has been demonstrated to reverse their cognitive decline. Dr. Dale Bredesen certainly uses a higher fat ketogenic diet in his protocol for Alzheimer's disease. I think it really gets to the notion of why a diet that's higher in sugar, higher in carbs, is so detrimental for the brain.

I mean that was our contention with the original 'Grain Brain' five years ago. Mechanistically, when you have elevated blood sugar, you're doing a lot of things, one of which is to compromise the insulin receptor. [Your insulin receptors] become resistant to the effects of insulin. We now know that insulin is far more important than simply helping your body deal with blood sugar.

The insulin receptor has dramatic effects in terms of its activity in the brain … to keep our brain cells healthy. As we start to compromise the ability of our brain to be receptive to insulin, by virtue of our elevated blood sugar, we see the powerful relationship that that has now with developing dementia," Perlmutter says.

Direct Relationship Between Elevated Blood Sugar and Dementia Has Been Proven

Another study cited in Perlmutter's book is a study5,6 published in 2013, which demonstrated a direct relationship between even subtle elevations of blood sugar and risk for developing dementia.

Other research7 published that same year also showed that sugar and other carbohydrates disrupt your brain function even if you have no symptoms of diabetes, primarily by shrinking your hippocampus, a brain region involved with the formation, organization and storage of memories.

A number of other studies support these findings, including a study8 published in the journal Diabetologia in January 2018, which found that the higher an individual's blood sugar, the faster their rate of cognitive decline. Perlmutter also cites a study in The Lancet, published in 2017, which found that an elevated A1C in average blood sugar is dramatically associated with shrinkage of the brain and risk for cognitive decline.

"We now get the fact that having elevated blood sugar increases inflammation," Perlmutter says. "As I'm sure your viewers well know, chronic inflammation is the cornerstone of about every degenerative condition you don't want to get, whether it's coronary artery disease, cancer or Alzheimer's. These are inflammatory conditions.

One study we have in the new book is from 2017, in the journal Neurology. It's a study that I think is profound. It took a group of individuals who were around their mid-50s, 1,600 of them, and measured the inflammation markers in their blood.

It followed these individuals for an incredible 24 years. What they found was there was a perfect linear relationship between those who had higher levels of inflammation 24 years ago and risk for developing dementia …

The implication is that people in their 40s and 50s who are overweight and have elevated blood sugar, both of which cause inflammation, are putting themselves at risk for an untreatable condition called Alzheimer's or dementia later in their lives …

Once that happens, there's very little that can be done, at least from a pharmaceutical perspective. So, the lifestyle choices that people make earlier in life are very, very relevant in terms of charting their brain's density as they get older."

Finding the Sweet Spot for Your Insulin Level

While the recommendation to keep your blood sugar and insulin levels low is a sound one, if you're doing this through nutritional ketosis, it's important not to go overboard. Many believe the best course of action is to stay in ketosis indefinitely and continuously.

"There is a tendency amongst some of us to say, 'If something's good, more is better.' I am personally guilty of overdoing things," he says. "But with respect to insulin, a study was recently published looking at 1,200 women followed for 34 years in Sweden, demonstrating that when you stratify these women in terms of their insulin level, there was a sweet spot, no pun intended.

Women at the high range of insulin had an increased risk for dementia, and women at the very, very low range of insulin as well had about a 2.68fold increased risk of developing dementia.

It's about the important role of insulin in the brain. It is a U-shaped curve. There are ideal levels for everything, whether it's alcohol consumption, exercise, sleep, et cetera. We know that too low blood sugar isn't good for you. With respect to the ketogenic diet, I think most people who are doing it are in and out of ketosis. I think that's reasonable."

Ketones and Your Brain

Nutritional ketosis benefits your brain in several different ways, but one of them is directly associated with the production of a ketone called beta-hydroxybutyrate. Not only is it a "superfuel" for your brain cells, beta-hydroxybutyrate also:

Directly improves insulin sensitivity

Changes gene expression for the better

Reduces chronic inflammation

Increases autophagy, the process by which your body rids itself of damaged cells

Enhances mitophagy, the process by which your body rids itself of defective mitochondria

A lot of this is newer data that was unavailable when "Grain Brain" first came out. The latest update does contain more details on this important ketone, including findings showing you can mildly increase beta-hydroxybutyrate simply by taking medium-chain triglyceride (MCT) oil, even if you're not restricting calories or cutting carbs.

"[MCT oil] paves the way for your liver to make beta-hydroxybutyrate," Perlmutter says, "so, you don't necessarily have to stress your body with calorie restriction or going deep in terms of lowering your blood sugar.

That said, [through a ketogenic diet] you'll gain the benefits of the beta-hydroxybutyrate, [and] … a little stress for your body, whether it's calorie restriction, fasting, lowering your blood sugar, diving into cold water [or] hot water … these are low levels of stress that turn out to activate gene pathways that are really good for you."

Exercise — The Only 'Drug' Worth Taking

Exercise is another really important factor that appears to play an enormous role in the development or prevention of Alzheimer's disease. One recent study9 demonstrated that aerobic exercise can actually offset the genetic risk associated with having the genetic markers for Alzheimer's.10

Other studies have shown exercise triggers a change in the way the amyloid precursor protein is metabolized,11 thus, slowing down the onset and progression of Alzheimer's, and increases levels of the protein PGC-1 alpha, thereby inhibiting production of toxic amyloid protein associated with Alzheimer's.

In one recent study,12 women with the highest cardiovascular fitness had a whopping 88 percent lower risk of dementia than those with moderate fitness. Even maintaining average fitness is worthwhile, as women with the lowest fitness had a 41 percent greater risk of dementia than those of average fitness.

Another fascinating study13,14 cited by Perlmutter was published December 2017 in the journal Neurology:

"The American Academy of Neurology (AAN) puts up practice guidelines for us neurologists. … The question that was raised, 'What should a neurologist do when dealing with a patient who has mild cognitive impairment (MCI)? [MCI] is really the first step toward developing Alzheimer's disease. They don't have Alzheimer's yet, but they're on their way.

It went through a list of 14 different drugs and all of the studies … and the quality of that research … What drug should we use? The conclusion from AAN, in their practice guidelines, was that the only thing we should recommend to patients is a drug called physical exercise.

This is breathtaking to me for a number of reasons: a) we've been saying that for a long time, and b) that a journal supported by [drug] advertising … would have the courage to publish that … under the level of scientific scrutiny, the only thing that can help slow the brain from declining is telling your patient to exercise — not writing them a prescription for aricept, memantine or other medications —is bold and heroic … and very positive."

Why Even Nongluten Grains Are Problematic

As implied by the name of Perlmutter's book, "Grain Brain," grains are problematic, courtesy of their ability to raise your insulin level, and this includes both gluten-containing and nongluten grains. Perlmutter explains:

"As it turns out, even the nongluten-containing grains are worrisome because of their carbohydrate load. Foods based upon corn, whatever it may be — processed corn, tortillas, you name it — are dramatic insults to your ability to regulate your blood sugar, and as such, pose a threat to your brain, immune system, risk for diabetes and, certainly, weight gain.

Beyond that, we have rice, which is also a seed grass, which defines it as a grain. Does it mean you shouldn't eat rice? No. Could you have a serving of rice? Absolutely. It should be wild, organic rice. There's some concern about rice in general being higher in arsenic — I'm aware of that.

Corn, by and large, is genetically modified. We need to avoid that. But if you have access to organic rice or corn and can limit the amount that you consume, based upon being concerned about the carbohydrate event, then you could have some on your plate."

Consider the Timing of Your Meals

The timing of your food intake is another factor that can have a significant impact on your health. As noted by Perlmutter, "This takes us to the area of what we call chronobiology. That is, [we need to try] to reconnect with the cycles of nature daily, seasonally and yearly, in terms of what we do to our bodies."

One important strategy is to eat dinner on the early side; definitely at least three hours before bedtime. "We don't want to be eating just before we go to sleep because of the blood sugar and insulin issue, and how that affects quality of sleep," Perlmutter says. Then, consider fasting for the remainder of the evening and night, until noon or 2 p.m. the following day.

"As you get more and more facile from a physiologic perspective, with respect to mobilizing fatty acids and using them as fuel, then protracting your breakfast to noon or 1 or 2 in the afternoon will get easier and easier," he says, adding:

"I think there's a lot said about doing that and also eating within an eight-hour window … and during the other 16 hours … you're not eating. That seems to have some really salubrious qualities about it as well …

I think the notion of getting into ketosis is important, done the right way. It doesn't mean abandoning all carbohydrates. One of the biggest issues I see is that individuals jump on this no-carb approach, eat more fat and protein, and they feel crappy. They feel constipated.

The reason is because they've abandoned a very important carbohydrate called dietary fiber. We don't want to do that. We want to make sure that this is a diet that's rich in dietary fiber and that we're getting adequate amounts of minerals, like magnesium, potassium and sodium …

We still want to emphasize that a variety of different-colored vegetables are good for you. Some people think that a ketogenic diet is basically Atkins redox. We're eating pork rinds, cheese and eggs all day. That's not what this is about.

You can be fully vegetarian and engage in a ketogenic diet easily by paying attention to fiber, minerals [and] adequate resources for B12, vitamin D and other B vitamins, just to make sure that you've covered the bases."

"I had the opportunity a few months ago to deliver a lecture at the World Bank, an international monetary fund, about the global impacts of Alzheimer's and other chronic degenerative conditions being based upon the Westernization of the global diet and why we need to really pay attention to this," Perlmutter says.

"I'm also looking forward to visiting the largest purveyor of food on planet Earth to give a lecture, and hope we can be influential in making some changes. What I'm saying is, the work continues. I think that it's work that has to be done even if it's a small percentage change in the destiny of global health. Because, boy, it sure is worth it."